The purpose of this project is to elucidate factors involved in the causation of gallstones and to evaluate methods for prevention and medical treatment of gallstones. The studies are based on the concept of lithogenic bile, namely, that gallstones occur when the concentrations of insoluble biliary constituents, especially cholesterol and bilirubins, exceed the capacity of solubilizing substances to hold them in solution. It is our view that the concept of lithogenic bile has been firmly established. While there is not a perfect correlation between the degree of supersaturation with an insoluble constituent and stone formation, there is nevertheless a strong statistical relationship. Our major efforts will be directed towards determining factors leading to supersaturation of bile with cholesterol and hence cholesterol gallstones. In these investigations, groups of patients who are at high risk for gallstone formation will be examined and patients with obesity, diabetes mellitus, hyperlipidemia, and women (in comparison to men). Also, various agents, either alone or in combination with chenodeoxycholic acid (CDCA) will be studied for their effects on bile lipid composition. These investigations may reveal new ways to prevent gallstone formation or to accelerate gallstone dissolution by use of agents in conjunction with CDCA. Finally, we will begin to explore the metabolism of bilirubin in bile. These investigations are made possible through the development of a technique to measure hepatic secretion of bilirubin. This technique may help to elicit mechanisms of pigment stone formation or stones with mixtures of cholesterol and pigment.